scholarly journals THE EQUILIBRIUM BETWEEN CYTOCHROME OXIDASE AND CARBON MONOXIDE

1957 ◽  
Vol 40 (4) ◽  
pp. 593-608 ◽  
Author(s):  
George Wald ◽  
David W. Allen
Keyword(s):  
Carbon Monoxide ◽  
Cytochrome Oxidase ◽  
Hill Equation ◽  
Bohr Effect ◽  
Degree Of Saturation ◽  
Percentage Saturation ◽  
Equilibrium Function ◽  
Hyperbolic Equilibrium ◽  
High Degree ◽  
The Hill

An evolution argument which attempted to trace the development of hemoglobins from such respiratory pigments as cytochrome oxidase presupposed that the latter possesses, in addition to its high affinity for oxygen, an approximately hyperbolic equilibrium function, and little if any Bohr effect (decline in affinity for oxygen with rise in acidity). Since cytochrome oxidase, unlike hemoglobin, is irreversibly oxidized by oxygen, the present experiments examine its combination with carbon monoxide, with which, like hemoglobin, it yields a true equilibrium. In all known hemoglobins the form of the equilibrium function and the vigor of the Bohr effect are similar with carbon monoxide and with oxygen, so that observations involving the former gas are relevant to the relations of the latter. The equilibrium function of cytochrome oxidase with carbon monoxide—percentage saturation vs. partial pressure of CO—is slightly inflected (in the Hill equation n = 1.26; for a hyperbola, n = 1). No Bohr effect is present in the range of pH 7–8. The pressure of carbon monoxide at which half-saturation occurs (p50) is about 0.17 mm. at 10–13°C. The affinity for carbon monoxide is therefore higher than commonly supposed. These properties are consistent with the evolution argument. They are important also for the physiological functioning of cytochrome oxidase, the nearly hyperbolic equilibrium function facilitating a high degree of saturation, and the lack of Bohr effect making this enzyme impervious to hyperacidity. The slight inflection of the equilibrium function shows that the Fe-porphyrin units of cytochrome oxidase interact to a degree, hence that the enzyme must contain more than one such unit per molecule. It is suggested that in cytochrome oxidase two Fe-porphyrin groups may unite with one oxygen in the manner Fe++-O2-Fe++; and that the evolution of hemoglobins proceeded over a first stage in which the hemes were separated so that each combines with only one molecule of oxygen, so tending to remain reduced; to a further stage in which the separated hemes interact through the protein to facilitate one another in combining with oxygen.

scholarly journals A hundred years of the Hill equation

2013 ◽  
Vol 35 (6) ◽  
pp. 40-43
Author(s):  
Paul C. Engel
Keyword(s):  
Carbon Monoxide ◽  
Nobel Laureate ◽  
Hill Equation ◽  
Classic Article ◽  
Biochemical Journal ◽  
The Hill

This BJ Classic article assesses the legacy of the Hill equation 100 years after the Nobel Laureate Archibald Hill published a paper entitled ‘The combinations of haemoglobin with oxygen and with carbon monoxide’1 in the Biochemical Journal.

scholarly journals THE OXYGEN EQUILIBRIUM OF THE HEMOGLOBIN OF THE EEL, ANGUILLA ROSTRATA

1951 ◽  
Vol 35 (1) ◽  
pp. 41-44 ◽  
Author(s):  
Austen Riggs
Keyword(s):  
Hill Equation ◽  
Anguilla Rostrata ◽  
Hill’S Equation ◽  
Oxygen Equilibrium ◽  
Equilibrium Function ◽  
Hill's Equation ◽  
The Hill

Kawamoto had reported that eel hemoglobin has a hyperbolic oxygen equilibrium function, with n in the Hill equation equal to 1. On the basis of Kawamoto's data and with new measurements, it is shown that the equilibrium function is in fact S-shaped, as in most other vertebrates, and n in Hill's equation equals 1.8.

scholarly journals Pharmacodynamics of Daptomycin against Enterococcus faecium and Enterococcus faecalis in the Murine Thigh Infection Model

2018 ◽  
Vol 62 (10) ◽  
Author(s):  
James M. Kidd ◽  
Kamilia Abdelraouf ◽  
Tomefa E. Asempa ◽  
Romney M. Humphries ◽  
David P. Nicolau
Keyword(s):  
Enterococcus Faecalis ◽  
Enterococcus Faecium ◽  
Hill Equation ◽  
Infection Model ◽  
Free Drug Concentration ◽  
Time Curve ◽  
Content Type ◽  
Concentration Time ◽  
The Hill ◽  
Susceptibility Breakpoint

ABSTRACT The Clinical and Laboratory Standards Institute (CLSI) daptomycin MIC susceptibility breakpoint for the treatment of enterococcal infections is ≤4 μg/ml. However, patients receiving daptomycin for the treatment of infections caused by enterococci with MICs of ≤4 μg/ml may experience treatment failures. We assessed the pharmacodynamics of daptomycin against enterococci in a neutropenic murine thigh infection model and determined the exposures necessary for bacteriostasis and a 1-log10-CFU reduction of Enterococcus faecalis and Enterococcus faecium. We further characterized daptomycin efficacy at clinically achievable exposures. Six E. faecium and 6 E. faecalis isolates (daptomycin MICs, 0.5 to 32 μg/ml) were studied. Daptomycin was administered at various doses over 24 h to achieve area under the free drug concentration-time curve-to-MIC ratios (fAUC0–24/MIC) ranging from 1 to 148. Daptomycin regimens that simulate mean human exposures following doses of 6, 8, and 10 mg/kg of body weight/day were also studied. Efficacy was assessed by the differences in the number of log10 CFU per thigh at 24 h. The Hill equation was used to estimate the fAUC0–24/MIC required to achieve bacteriostasis and a 1-log10-CFU reduction. For E. faecium, a 1-log10-CFU reduction required an fAUC0–24/MIC of 12.9 (R2 = 0.71). For E. faecalis, a 1-log10-CFU reduction was not achieved, while the fAUC0–24/MIC required for stasis was 7.2 (R2 = 0.8). With a human-simulated regimen of 6 mg/kg/day, a 1-log10-CFU reduction was observed in 3/3 E. faecium isolates with MICs of <4 μg/ml and 0/3 E. faecium isolates with MICs of ≥4 μg/ml; however, a 1-log10-CFU reduction was not achieved for any of the 6 E. faecalis isolates. These results, alongside clinical data, prompt a reevaluation of the current breakpoint.

Effect of osmotic swelling and shrinkage on Na(+)-K+ pump activity in mammalian cardiac myocytes

1993 ◽  
Vol 265 (5) ◽  
pp. C1201-C1210 ◽  
Author(s):  
D. W. Whalley ◽  
L. C. Hool ◽  
R. E. Ten Eick ◽  
H. H. Rasmussen
Keyword(s):  
Ventricular Myocytes ◽  
Pump Current ◽  
Hill Equation ◽  
Cell Swelling ◽  
Intracellular Na Activity ◽  
Single Ventricular Myocytes ◽  
Hyperosmolar Solutions ◽  
Hill Coefficients ◽  
The Hill ◽  
The Relationship

The effect on the sarcolemmal Na(+)-K+ pump of exposure to anisosmolar solutions was examined using whole cell patch clamping and ion-selective microelectrodes. Na(+)-K+ pump currents were measured in single ventricular myocytes by using pipette Na+ concentrations ([Na]pip) of 0-70 mM. The relationship between [Na]pip and pump current was well described by the Hill equation. The [Na]pip for half-maximal pump current (K0.5) was 21.4 mM in isosmolar (310 mosM) solution. K0.5 was 12.8 mM during cell swelling in hyposmolar solution (240 mosM) and 39.0 mM during cell shrinkage in hyperosmolar solution (464 mosM). The maximal pump currents, derived from the best fit of the Hill equation, and the Hill coefficients were similar in isosmolar, hyposmolar, and hyperosmolar solutions. A sustained (> 20 min) decrease in the intracellular Na+ activity developed during exposure of intact papillary muscles to hyposmolar solutions, and a sustained increase developed during exposure to hyperosmolar solutions. We conclude that osmotic myocyte swelling stimulates the sarcolemmal Na(+)-K+ pump at near-physiological levels of intracellular Na+, whereas shrinkage inhibits the pump. These changes are due to increases and decreases, respectively, in the apparent affinity of the pump for Na+.

Perspective on the relationship between GABAA receptor activity and the apparent potency of an inhibitor

2021 ◽  
Vol 19 ◽  
Author(s):  
Allison L. Germann ◽  
Spencer R. Pierce ◽  
Alex S. Evers ◽  
Joe Henry Steinbach ◽  
Gustav Akk
Keyword(s):  
Gabaa Receptor ◽  
Hill Equation ◽  
Response Relationship ◽  
Inhibition Concentration ◽  
Level Of Activity ◽  
Control Response ◽  
The Hill ◽  
The Relationship ◽  
Inhibition Curve ◽  
Receptor Channel

Background : In electrophysiological experiments inhibition of a receptor-channel, such as the GABAA receptor, is measured by co-applying an agonist producing a predefined control response with an inhibitor to calculate the fraction of the control response remaining in the presence of the inhibitor. The properties of the inhibitor are determined by fitting the inhibition concentration-response relationship to the Hill equation to estimate the midpoint (IC50) of the inhibition curve. Objective: We sought to estimate here the sensitivity of the fitted IC50 to the level of activity of the control response. Methods: The inhibition concentration-response relationships were calculated for models with distinct mechanisms of inhibition. In Model I, the inhibitor acts allosterically to stabilize the resting state of the receptor. In Model II, the inhibitor competes with the agonist for a shared binding site. In Model III, the inhibitor stabilizes the desensitized state. Results: The simulations indicate that the fitted IC50 of the inhibition curve is sensitive to the degree of activity of the control response. In Models I and II, the IC50 of inhibition was increased as the probability of being in the active state (PA) of the control response increased. In Model III, the IC50 of inhibition was reduced at higher PA. Conclusions: We infer that the apparent potency of an inhibitor depends on the PA of the control response. While the calculations were carried out using the activation and inhibition properties that are representative of the GABAA receptor, the principles and conclusions apply to a wide variety of receptor-channels.

Influence of carbon monoxide on hemoglobin-oxygen binding

1976 ◽  
Vol 41 (6) ◽  
pp. 893-899 ◽  
Author(s):  
M. P. Hlastala ◽  
H. P. McKenna ◽  
R. L. Franada ◽  
J. C. Detter
Keyword(s):  
Carbon Monoxide ◽  
Oxygen Affinity ◽  
Co2 Concentration ◽  
Bohr Effect ◽  
Oxygen Binding ◽  
Dissociation Curve ◽  
Low Oxygen ◽  
Oxygen Dissociation ◽  
Initial Binding ◽  
Fixed Acid

The oxygen dissociation curve and Bohr effect were measured in normal whole blood as a function of carboxyhemoglobin concentration [HbCO]. pH was changed by varying CO2 concentration (CO2 Bohr effect) or by addition of isotonic NaOH or HCl at constant PCO2 (fixed acid Bohr effect). As [HbCO] varied through the range of 2, 25, 50, and 75%, P50 was 26.3, 18.0, 11.6, and 6.5 mmHg, respectively. CO2 Bohr effect was highest at low oxygen saturations. This effect did not change as [HbCO] was increased. However, as [HbCO] was increased from 2 to 75%, the fixed acid Bohr factor increased in magnitude from -0.20 to -0.80 at very low oxygen saturations. The effect of molecular CO2 binding (carbamino) on oxygen affinity was eliminated at high [HbCO]. These results are consistent with the initial binding of O2 or CO to thealpha-chain of hemoglobin. The results also suggest that heme-heme interaction is different for oxygen than for carbon monoxide.

scholarly journals Kinetic studies on two isoforms of acetyl-CoA carboxylase from maize leaves

1996 ◽  
Vol 318 (3) ◽  
pp. 997-1006 ◽  
Author(s):  
Derek HERBERT ◽  
Lindsey J PRICE ◽  
Claude ALBAN ◽  
Laure DEHAYE ◽  
Dominique JOB ◽  
...  
Keyword(s):  
Kinetic Studies ◽  
Product Inhibition ◽  
Hill Equation ◽  
Acetyl Coa Carboxylase ◽  
Acetyl Coa ◽  
Maize Leaves ◽  
Ic50 Values ◽  
A Minor ◽  
The Hill

The steady-state kinetics of two multifunctional isoforms of acetyl-CoA carboxylase (ACCase) from maize leaves (a major isoform, ACCase1 and a minor isoform, ACCase2) have been investigated with respect to reaction mechanism, inhibition by two graminicides of the aryloxyphenoxypropionate class (quizalofop and fluazifop) and some cellular metabolites. Substrate interaction and product inhibition patterns indicated that ADP and Pi products from the first partial reaction were not released before acetyl-CoA bound to the enzymes. Product inhibition patterns did not match exactly those predicted for an ordered Ter Ter or a random Ter Ter mechanism, but were close to those postulated for an ordered mechanism. ACCase2 was about 1/2000 as sensitive as ACCase1 to quizalofop but only about 1/150 as sensitive to fluazifop. Fitting inhibition data to the Hill equation indicated that binding of quizalofop or fluazifop to ACCase1 was non-cooperative, as shown by the Hill constant (napp) values of 0.86 and 1.16 for quizalofop and fluazifop respectively. Apparent inhibition constant values (K´ from the Hill equation) for ACCase1 were 0.054 µM for quizalofop and 21.8 µM for fluazifop. On the other hand, binding of quizalofop or fluazifop to ACCase2 exhibited positive co-operativity, as shown by the napp values of 1.85 and 1.59 for quizalofop and fluazifop respectively. K´ values for ACCase2 were 1.7 mM for quizalofop and 140 mM for fluazifop. Kinetic parameters for the co-operative binding of quizalofop to maize ACCase2 were close to those of another multifunctional ACCase of limited sensitivity to graminicide, ACC220 from pea. Inhibition of ACCase1 by quizalofop was mixed-type with respect to acetyl-CoA or ATP, but the concentration of acetyl-CoA had the greater effect on the level of inhibition. Neither ACCase1 nor ACCase2 was appreciably sensitive to CoA esters of palmitic acid (16:0) or oleic acid (18:1). Approximate IC50 values were 10 µM (ACCase2) and 50 µM (ACCase1) for both CoA esters. Citrate concentrations up to 1 mM had no effect on ACCase1 activity. Above this concentration, citrate was inhibitory. ACCase2 activity was slightly stimulated by citrate over a broad concentration range (0.25–10 mM). The significance of possible effects of acyl-CoAs or citrate in vivo is discussed.

scholarly journals An approach based on diffusion to study ligand-macromolecule interaction.

2002 ◽  
Vol 49 (3) ◽  
pp. 703-707 ◽  
Author(s):  
Mohammad R Housaindokht ◽  
Mahmood Bahrololoom ◽  
Shirin Tarighatpoor ◽  
Ali A Mossavi-Movahedi
Keyword(s):  
Methyl Orange ◽  
Diffusion Process ◽  
Binding Constant ◽  
Phosphate Buffer ◽  
Binding Capacity ◽  
Free Ligand ◽  
Hill Equation ◽  
New Approach ◽  
Binding Isotherm ◽  
The Hill

A new approach has been developed to study binding of a ligand to a macromolecule based on the diffusion process. In terms of the Fick's first law, the concentration of free ligand in the presence of a protein can be determined by the measurement of those ligands which are diffused out. This method is applied to the study of binding of methyl-orange to lysozyme in phosphate buffer of pH 6.2, at 30 degrees C. The binding isotherm was determined initially, followed by application of the Hill equation to the data obtained, then binding constant and binding capacity were estimated.

Myoglobin oxygen dissociation by multiwavelength spectroscopy

1997 ◽  
Vol 82 (1) ◽  
pp. 86-92 ◽  
Author(s):  
Kenneth A. Schenkman ◽  
David R. Marble ◽  
David H. Burns ◽  
Eric O. Feigl
Keyword(s):  
Least Squares ◽  
Hill Equation ◽  
Oxygen Binding ◽  
Dissociation Curve ◽  
Nitrogen Gas ◽  
Binding Characteristics ◽  
Oxygen Fraction ◽  
Oxygen Dissociation ◽  
Dissociation Curves ◽  
The Hill

Schenkman, Kenneth A., David R. Marble, David H. Burns, and Eric O. Feigl. Myoglobin oxygen dissociation by multiwavelength spectroscopy. J. Appl. Physiol. 82(1): 86–92, 1997.—Multiwavelength optical spectroscopy was used to determine the oxygen-binding characteristics for equine myoglobin. Oxygen-binding relationships as a function of oxygen tension were determined for temperatures of 10, 25, 35, 37, and 40°C, at pH 7.0. In addition, dissociation curves were determined at 37°C for pH 6.5, 7.0, and 7.5. Equilibration was achieved with a myoglobin solution, at the desired temperature and pH, and 16 oxygen-nitrogen gas mixtures of known oxygen fraction. Correction for the inevitable presence of metmyoglobin was made by using a three-component least squares analysis and by correcting the end point oxymyoglobin spectra for the presence of metmyoglobin. The[Formula: see text] at which myoglobin is half-saturated with O2(P50) was determined to be 2.39 Torr at pH 7.0 and 37°C. The myoglobin dissociation curve was well fit by the Hill equation [saturation =[Formula: see text]/([Formula: see text]+ P50)].

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